PROJECT SUMMARY/ABSTRACT People living with HIV (PLWH) and the elderly more susceptible to potentially fatal complications from influenza (such as pneumonia) and invasive Streptococcus pneumoniae bacteremia and meningitis. Age-associated B cell defects compound HIV-induced B cell dysfunction to severely compromise humoral immune responses to influenza viruses and pneumococcus. Routine vaccinations against influenza and pneumococcus are therefore recommended in these populations but antibody responses to these vaccinations are poor and ineffective. Strategies to improve B cell function and boost humoral immune responses to infection and vaccination are therefore needed to improve health outcomes for the aging HIV/AIDS population. Bisphosphonates (BPs), inhibitors of bone resorption used in the treatment of skeletal disorders including osteoporosis, unexpectedly improved humoral immune responses in mice and also increased total IgG levels in humans with Paget's disease of bone. This suggests that BPs can act as B cell-targeting adjuvants to boost antibody responses, but the mechanism is unknown. My ongoing K01 is leveraging this observation in a pilot study to investigate if the BP Zoledronic Acid (ZA) can reverse HIV-induced B cell dysfunction and improve antibody responses to infection and vaccination. Our data indeed reveal that ZA significantly boosted anti- influenza A IgG antibody levels in immunized HIV-infected individuals (aged 30-50) by 32%, compared to only 8% in the placebo group. The mechanism underlying this boost in antibody responses and whether it occurs in individuals PLWH >50 years old is unknown. Also, the ability of oral BPs such as Alendronate and Ibandronate, which are even more widely used in clinical practice, to boost humoral immunity in PLWH, is unknown. The aim of this R03 project is to gain a better understanding of the potential mechanisms by which BPs boost antigen- specific antibody responses. We will leverage samples from BP-treated and non-BP-treated HIV- and HIV+ male and female participants enrolled in the NHLBI-funded Combined Cohort Study (CCS) to show that BPs boost humoral immunity to clinically-relevant viral (influenza) and bacterial (pneumococcus) antigens by enhancing B cell maturation and function. These studies extend my ongoing K01 project and add essential mechanistic endpoints to generate robust data in support of my future R01 application investigating the molecular mechanisms of BP-mediated enhanced humoral immunity in aging PLWH.